title: Sodium meta-arsenite induces reactive oxygen species-dependent apoptosis, necrosis, and autophagy in both androgen-sensitive and androgen-insensitive prostate cancer cells.
abstract: Sodium meta-arsenite (NaAsO2), a novel compound synthesized by Komipham International Co. Ltd, is an orally bioavailable, water-soluble trivalent arsenical that has shown potent cytotoxic activity in human solid cancer cells in vitro and in vivo, and is currently undergoing phase I/II clinical trials for the treatment of prostate cancer. In this study, mechanisms of cell death induced by sodium meta-arsenite were investigated. Sodium meta-arsenite reduced cell viability and increased the sub-G1 population in cell cycle analysis in both androgen-sensitive LNCaP and androgen-insensitive CWR22RV1 cells. The apoptosis induced by sodium meta-arsenite was associated with cleavage of caspases 3, 8, and 9, and poly (ADP-ribose) polymerase (PARP) and increased annexin V-positive cells, and was inhibited by the pan-caspase inhibitor Z-VAD-fmk. Sodium meta-arsenite also increased the level of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and the number of autophagic vacuoles as shown by electron microscopy. Both the autophagy inhibitor 3-methyladenine and the necrosis inhibitor necrostatin-1 blocked cell death induced by sodium meta-arsenite. Moreover, sodium meta-arsenite led to the accumulation of intracellular reactive oxygen species (ROS) and N-acetyl-L-cysteine (NAC), a ROS scavenger, decreased sodium meta-arsenite-induced levels of cleaved PARP and LC3-II. Propidium iodide (PI) staining also showed that NAC restored membrane integrity, damaged by sodium meta-arsenite. Therefore, these results suggest that sodium meta-arsenite induces apoptotic, necrotic, and autophagic cell death through intracellular ROS accumulation in both androgen-sensitive and androgen-insensitive prostate cancer cells and may be used as a new anticancer drug for the treatment of prostate cancer.
authors.affiliation: aDepartment of Urology bInstitute for Innovative Cancer Research cDepartment of Medicine, Graduate School dDepartment of Medicine eAsan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul fPharmaceutical Division, Komipharm International Co. Ltd, Shiheung, Korea.
authors.forename: Yunlim
authors.initials: Y
authors.lastname: Kim
authors.forename: In Gab
authors.initials: IG
authors.lastname: Jeong
authors.forename: Dalsan
authors.initials: D
authors.lastname: You
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Song
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.forename: Sung-Wuk
authors.initials: SW
authors.lastname: Jang
authors.forename: Sujong
authors.initials: S
authors.lastname: Kim
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Choung-Soo
authors.initials: CS
authors.lastname: Kim
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D009336:Necrosis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017670:Sodium Compounds / Q000494:pharmacology*
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D018053:Arsenites; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; C017947:sodium arsenite